Bacteriophages (phages) are a phylum of viruses that infect bacteria, and are distinct from the animal and plant viruses. Phages can have either a “lytic” life cycle, a “lysogenic” life cycle that can potentially become lytic, or a “non-lytic” life cycle. Phages replicating through the lytic cycle cause lysis of the host bacterial cell as a normal part of their life cycles. Phages replicating through the lysogenic cycles are called temperate phages, and can either replicate by means of the lytic life cycle and cause lysis of the host bacterium, or they can incorporate their DNA into the host bacterial DNA and become noninfectious prophages.
The natural capability of phages to infect and kill bacteria, together with the specificity of the phage-bacterial interactions, is the basic phenomena on which the concept of phage therapy is built. Therefore, phages that possess lytic life cycle are the most suitable candidates for phage therapy.
Phage therapy was first proposed by D'herelle (D'herelle 1922. The bacteriophage: its role in immunity. Williams and Wilkens Co. Waverly Press Baltimore USA), showing promise but also arousing much controversy. Since the introduction of antibiotics in the 1940s, little attention was paid to this field of therapeutics, especially in the Western world. The main reason for this lack of interest was the fact that none of the potential experimental therapeutic uses has resulted in the formulation of an efficacious bacteriophage composition, i.e., one that is sufficiently virulent, non-toxic, host-specific, and yet with a wide enough host range to be of practical use.
The extensive use of antibiotics has led to an increase in the number of bacterial strains resistant to most or all available antibiotics, causing increasingly serious problems and raising widespread fears of return to a pre-antibiotic era of untreatable infections and epidemics.
The newfound ability to sequence entire microbial genomes and to determine the molecular bases of pathogenicity may open new avenues for treating infectious diseases, but other approaches are also being sought with increasing fervor. One such approach is the technology of bacteriophage therapy, which is attracting renewed attention in the West as a potential weapon against drug-resistant microbes and hard-to-treat infection (Stone R 2002 Science 298:728-731).
With the fast development in the field of molecular biology, much attention has been devoted to phages as research tools. Today phages are widely used for the identification of bacteria types and in various molecular biology techniques, and good laboratory practice is available for the isolation of highly pure phage compositions.
These newly developed techniques have been also used in the field of phage therapy. For example, International Patent Application No. WO 00/69269 discloses the use of certain phage strain for treating infections caused by Vancomycin-sensitive as well as resistant strains of Enterococcus faecium, and International Patent Application No. WO 01/93904 discloses the use of bacteriophage, alone or in combination with other anti-microbial means, for preventing or treating gastrointestinal diseases associated with the species of the genus Clostridium. 
US Patent Application No. 2001/0026795 describes methods for producing bacteriophage modified to delay inactivation by the host defense system, and thus increasing the time period in which the phage is active in killing the bacteria.
US Patent Application No. 2002/0001590 discloses the use of phage therapy against multi-drug resistant bacteria, specifically methicillin-resistant Staphylococcus aureus, and International Patent Application No. WO 02/07742 discloses the development of bacteriophage having multiple host range.
The use of phage therapy for the treatment of specific bacterial-infectious disease is disclosed, for example, in US Patent Application Nos. 2002/0044922; 2002/0058027 and International Patent Application No. WO 01/93904.
However, commercial scale production of bacteriophage compositions for therapeutic use is still limited. In current techniques, the titer of the phage composition is low, usually in the range of 109-1011 pfu/ml on a laboratory scale, and 107-109 on a commercial scale, whereas the titer typically required for phage therapy is 1012 pfu/ml. Additionally, to reach the desirable titer, very large volumes of liquid are required.
As described herein below, the dosage for phage therapy is in the range of 106 to 1013 pfu/Kg body weight/day, with 1012 pfu/Kg body weight/day suggested to be a preferable dosage. According to the currently common liquid culture methods for phage growth, reaching one daily dose of bacteriophage therapy per person would require a liquid volume of 5-10 liters. Commercial production of phage stock composition of one specific phage type would therefore involve growth at volumes of thousands of liters with the need of multiple uses of large-volume fermenters.
The large volume of liquid also requires the use of large fermenters that are difficult and expensive to operate. Moreover, the subsequent processes of phage purification, at least in part, are also performed with large liquid volumes, making working under good manufacturing practice (GMP), necessary for the production of pharmaceutical compositions, very hard to achieve.
In fact, a common estimation is that the clinical trials in the field of phage therapy would be very expensive, the reason being the benefit of using a phage “cocktail” for efficient treatment, with the need to prepare each phage separately in the special GMP facilities required for FDA approval. This, in turn, means that phage therapy will be relatively expensive, at least initially.
Therefore, there is a recognized need for, and it would be highly advantageous to have a method for commercial production of phage compositions that elevates yield titer, reduces manufacturing volume and enables the application of low-volume well-developed purification processes to the obtained phage extract.